This study concerns an investigation of the role of a putative endogenous ligand for the 5-HT2 recognition site. We have identified a peptide isolated from bovine brain which appears to specifically inhibit the binding of 3H-ketanserin to the 5-HT2 recognition site. This peptide has a molecular weight of about 6,000 daltons and specifically inhibits the binding of 3H-ketanserin and 3H-mianserin (another 5-HT2 specific ligand) but it does not inhibit the 3H-imipramine or 3H-dihydroalprenolol (a Beta-adrenergic specific ligand) binding. Incubation of active peptide fractions with a protease (either trypsin or pronase) diminishes the activity of the peptide. The peptide has been partially purified by ion-exchange chromatography (carboxymethyl-sephadex), molecular sieve chromatography (Biogel P-10), reverse-phase chromatography (ODS) and high pressure liquid chromatography (reverse phase C8). As little as 3 g of partially purified material inhibits greater than 50% of specific 3H-ketanserin binding. We are currently testing the biologic activity of this peptide by ascertaining its effects on adenylate cyclase activity and the effect of the peptide on 5-HT stimulated phosphatidylinositol hydrolysis. Since 5-HT2 recognition sites are down-regulated by chronic antidepressant treatment in experimental animals this putative endocoid might be involved in the therapeutic effects of antidepressants.